Linked Life Data

15355987

Source:http://linkedlifedata.com/resource/pubmed/id/15355987

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
50
pubmed:dateCreated
2004-12-6
pubmed:abstractText
Extracellular zinc promotes cell proliferation and its deficiency leads to impairment of this process, which is particularly important in epithelial cells. We have recently characterized a zinc-sensing receptor (ZnR) linking extracellular zinc to intracellular release of calcium. In the present study, we addressed the role of extracellular zinc, acting via the ZnR, in regulating the MAP kinase pathway and Na+/H+ exchange in colonocytes. We demonstrate that Ca2+ release, mediated by the ZnR, induces phosphorylation of ERK1/2, which is highly metal-specific, mediated by physiological concentrations of extracellular Zn2+ but not by Cd2+, Fe2+, Ni2+, or Mn2+. Desensitization of the ZnR by Zn2+, is followed by approximately 90% inhibition of the Zn2+ -dependent ERK1/2 phosphorylation, indicating that the ZnR is a principal link between extracellular Zn2+ and ERK1/2 activation. Application of both the IP3 pathway and PI 3-kinase antagonists largely inhibited Zn2+ -dependent ERK1/2 phosphorylation. The physiological significance of the Zn2+ -dependent activation of ERK1/2 was addressed by monitoring Na+/H+ exchanger activity in HT29 cells and in native colon epithelium. Preincubation of the cells with zinc was followed by robust activation of Na+/H+ exchange, which was eliminated by cariporide (0.5 microm); indicating that zinc enhances the activity of NHE1. Activation of NHE1 by zinc was totally blocked by the ERK1/2 inhibitor, U0126. Prolonged acidification, in contrast, stimulates NHE1 by a distinct pathway that is not affected by extracellular Zn2+ or inhibitors of the MAP kinase pathway. Desensitization of ZnR activity eliminates the Zn2+ -dependent, but not the prolonged acidification-dependent activation of NHE1, indicating that Zn2+ -dependent activation of H+ extrusion is specifically mediated by the ZnR. Our results support a role for extracellular zinc, acting through the ZnR, in regulating multiple signaling pathways that affect pH homeostasis in colonocytes. Furthermore activation of both, ERK and NHE1, by extracellular zinc may provide the mechanism linking zinc to enhanced cell proliferation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
51804-16
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Extracellular zinc triggers ERK-dependent activation of Na+/H+ exchange in colonocytes mediated by the zinc-sensing receptor.
pubmed:affiliation
Department of Morphology, Zlotowski Center for Neuroscience and the Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't